The objective of this research is the elucidation of the molecular events in tumor cells of pituitary and nonpituitary origin by which the synthesis, storage, and secretion of certain polypeptide hormones are regulated. In particular, it is concerned with the biosynthetically related series of hormones derived from the common precursor, pro-opiolipomelanocortin (proOLMC): adrenocorticotropin (ACTH), beta-lipoprotein (beta LPH), gamma LPH, beta-melanocyte-stimulating hormone (beta MSH), and beta-endorphin (beta END). We have examined both intra-adrenal pheochromocytoma and normal adrenal medullary tissues obtained at the time of surgery for the presence of immunoreactive (IR)-proOLMC peptides and the hypothalamic peptide, corticotropin-releasing hormone (CRH), that stimulates proOLMC peptide secretion by the pituitary gland. We have found all of the proOLMC peptides in both normal and neoplastic adrenomedullary extracts. Furthermore, we found IR-alpha MSH, indicating that processing of proOLMC in this extrapituitary site is more like that in the intermediate lobe of the normal pituitary gland than in the anterior lobe. We also found IR-CRH that had similar molecular size on gel filtration analysis but consisted of about equal parts of intact and Met21-O-CRH as analyzed by reverse-phase HPLC. The intact CRH had full bio-logic activity in a dispersed rat anterior pituitary cell column perifusion assay. None of these patients had clinical evidence for ectopic ACTH or CRH production. The physiological significance of the coexistence in the adrenal medulla of proOLMC peptides with CRH, their releasing hormone in the pituitary, and of the presence of proOLMC peptides adjacent to the adrenal cortex, whose function they help regulate, remains to be elucidated. However, our data do suggest that "ectopic" production of ACTH by adrenomedullary tumors is more appropriately termed "inappropriate." (C)